Catabolism of extracellular glutathione is a driver of metastasis formation
Extracellular glutathione catabolism may play a critical role in supporting cancer cell proliferation and survival during metastasis, particularly in the liver.
Where it sits
this study against the rest of the glutathione (gsh) corpusSummary and findings
This study examined the role of extracellular glutathione (GSH) catabolism in cancer metastasis, particularly in the liver microenvironment. It was found that cancer cells degrade GSH to provide cysteine for proliferation. The study involved murine breast cancer cells and human breast cancer patient data.
Abstract
Metastasizing cancer cells require metabolic plasticity to adapt to the microenvironment of the target organ. Analyzing metabolites in interstitial fluids, we found that the liver microenvironment is devoid of cystine but contains high concentrations of glutathione (GSH). Detailed mechanistic analysis revealed that cancer cells degrade extracellular GSH utilizing gamma-glutamyl-transferase (GGT) activity for provision of cysteine to support proliferation and prevent ferroptosis under cystine-free conditions. This was independent of system Xc- but required activity of glutamate-cysteine ligase (GCLC). GGT1 expression was associated with poor survival and upregulated in liver metastases of human breast cancer patients. Overexpression of Ggt1 in murine breast cancer cells enhanced their capacity for liver colonization and promoted lung metastases after orthotopic implantation. This identifies extracellular GSH catabolism as driver of metastasis that supports proliferation and oxidative stress resistance in metabolically challenging microenvironments.
Background
Not reported in abstract.
Methods
Not reported in abstract.
Results
Not reported in abstract.
Interpretation
Not reported in abstract.
Limitations
Not reported in abstract.